Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

Nelson and the rapid autopsy program at the University of Washington analyzed 176 primary or metastatic tumors from 63 men with metastatic prostate cancer using whole exome sequencing, array CGH, and expression profiling. Integrating copy number changes, mutations, and gene expression, they found that metastases from the same individual were highly concordant. Surprisingly, there was less than 5% discordance between metastases for a particular driver aberration in the cohort of patients they sampled. Men with DNA repair mutations treated with the DNA-damaging agent carboplatin had more durable responses than men without DNA repair mutations. The provocative data from this comprehensive analysis of prostate cancers revealed that evaluation of a single metastasis provides a reasonable indication of the driver genomic alterations that are present within an individual patient with multiple metastases.Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 2016;22:369–78.The serine/threonine kinase polo-like kinase 1 (PLK1), a key cell cycle regulator, is involved in the development of prostate cancer. However, how PLK1 relates to cancer development is largely unknown. Wu and colleagues demonstrate that overexpression of PLK1 in prostate epithelial cells initated oncogenic transformation. PLK1 dramatically changed transcriptional programming of the cells, caused epithelial-mesenchymal transition, and drove cell migration and invasion. Conversely, PLK1 silencing enhanced epithelial characteristics and inhibited cell motility in metastatic prostate cancer cells. PLK1 mediated these functional changes by phosphorylating CRAF, which stimulated downstream MEK1/2-ERK1/2-FRA1-ZEB1/2 signaling pathways. Thus, the authors identified unique noncanonical functions of PLK1 and clarified the relevant underlying signaling mechanisms.Wu J, Ivanov AI, Fisher PB, Zheng F. Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling. Elife 2016 Mar 22;5. doi: 10.7554/eLife.10734.Bhoopathi and colleagues identified a novel signaling mechanism by which melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL24) induces caspase-independent apoptosis in neuroblastoma cells. Utilizing a tropism-modified cancer terminator virus (Ad.5/3-CTV) that specifically replicates in cancer cells producing mda-7/IL24, the authors assessed relevance in neuroblastoma. Ad.5/3-CTV inhibited proliferation and induced apoptosis in a caspase-3/9–independent manner, inducing apoptosis-inducing factor (AIF) translocation to the nucleus. Ad.5/3-CTV–mediated cell death could be rescued by inhibiting AIF. Neuroblastoma cells infected with Ad.5/3-CTV increased phosphorylation of ATM, resulting in nuclear translocation and increased γ-H2AX, which further inhibited AIF changes. These findings set the path for potential combinatorial approaches that may be used to effectively treat patients with advanced neuroblastoma.Bhoopathi P, Lee N, Pradhan AK, Shen X-N, Das SK, Sarkar D, et al. mda-7/IL-24 induces cell death in neuroblastoma through a novel mechanism involving AIF and ATM. Cancer Research; Published OnlineFirst April 13, 2016; doi:10.1158/0008-5472.CAN-15-2959.Androgen deprivation therapy (ADT), castration, and androgen receptor (AR) antagonists are standard of care for metastatic prostate cancer. More potent AR antagonists such as enzalutamide improve survival, while successful immunotherapy in other cancers has led to clinical trials combining hormonal therapy with immunotherapies. A preclinical study from Pu and colleagues suggests that AR antagonists used in the clinic, including enzalutamide, impair T-cell priming and may blunt subsequent adaptive immune responses in prostate cancer models in vitro and in vivo. This immunosuppression was independent of the AR, involved chloride channel-dependent impairment of T-cell cytokine production, and likely represents an off-target effect on GABA-A signaling in T-cells. These novel findings emphasize the need for preclinical studies to help guide the most rational clinical trial combinations of immunotherapies with standard-of-care treatments in cancer.Pu Y, Xu M, Liang Y, Yang K, Guo Y, Yang X, et al. Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse. Sci Transl Med 2016;8:333ra47.Tissue fibrosis confounds treatment of pancreatic ductal carcinoma (PDAC), impairing drug response, reducing immune cell accessibility, and driving aggressive disease. Laklai and colleagues reveal an association between patient survival and tumor cell tension [phosphoMLC2 (MYL9) levels], thickness of adjacent collagen fibrils, and compromised TGFβ signaling (phospho-SMAD2 levels) in human biopsies. In agreement with these clinical findings, thicker collagen bundles, a stiffer periductal matrix, and a more contractile PDAC epithelium (increased phosphoMLC2 and integrin-dependent mechanosignals) were observed in PDAC models with reduced epithelial TGFβ signaling (KTC mice) as opposed to PDACs harboring gain-of-function p53 mutations (KPC mice). These data suggest that although fibrosis universally accompanies pancreatic transformation, the nature of the fibrotic response can be highly dependent on the genotype of the tumor.Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 2016 Apr 18. doi: 10.1038/nm.4082. [Epub ahead of print].In Ptch+/−-driven mouse models for medulloblastoma, all mice show aberrant proliferation of cerebellar granule cell precursors, but only some develop advanced medulloblastoma. Tamayo-Orego and colleagues studied P7 external granule layer, preneoplastic lesions, and advanced medulloblastoma, and found high levels of p16Ink4a (CDKN2A) and p21 (CDKN1A) only in the preneoplastic lesions. A third of advanced medulloblastoma harbored p53 mutations, which they could replicate in other SHH models of medulloblastoma. By laser microdissection over time, Ptch1 loss of heterozygosity was the first event in preneoplastic lesions, followed by p53 mutations. In samples without p53 mutations, 60% harbored p16ink4a inactivation. They confirmed similar inactivation of p16INK4A (CDKN2A) in human SHH medulloblastoma. This study provides developmental insights into evasion of oncogene-induced senescence in advanced medulloblastoma.Tamayo-Orrego L, Wu CL, Bouchard N, Khedher A, Swikert SM, Remke M, et al. Evasion of cell senescence leads to medulloblastoma progression. Cell Reports 2016;14:2925–37.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.